The cellular and molecular events in limb development are being studied in mouse embryos. The techniques used required both histologic analyses and biochemical assays. The primary morphological tool is Golgi staining which permits studies of cell polarity as the Golgi apparatus occupies the pole of the cell from which material is secreted. Studies to date have shown the epithelium is always oriented away from the underlying mesenchyme. The mesenchyme beneath the epithelium shifts its polarity on days 12 to 13 (the time of chondrogenesis) to point primarily toward the epithelium. Mesenchyme cells aggregating prior to forming bone are oriented primarily toward the longitudinal axis of the aggregate. The types of collagen in the developing limb are also being determined. We have found that three small molecular weight hydroxyproline-containing compounds are present during limb development. These are much more abundant than large molecules like collagen which also contain hydroxyproline. These compounds are present as polypeptides. These morphologic and biochemical studies are also being carried out on mouse limbs malformed by the dominant gene Dh (dominant hemimelia). It is proposed that the single mutant gene malformation will interrupt primarily one aspect of limb morphogenesis. By comparing different hereditary limb malformations one would expect to find primary effects on different aspects of the same process. Specimens from human limb malformations are being studied to see if they contain abnormal or immature types of collagen.